ULK4 and BRWD3 deletions have been identified in patients with developmental/language delay and intellectual disability. Both genes play pivotal roles in brain development. In particular, ULK4 encodes serine/threonine kinases that are critical for the development and function of the nervous system, while BRWD3 plays a crucial role in ubiquitination, as part of the ubiquitin/proteasome system. We report on 2 brothers, aged 7.6 and 20 years, presenting with cognitive impairment, epilepsy, autistic features, hearing loss, and obesity. Array-CGH analysis demonstrated 2 rare CNVs in both siblings: a paternally inherited microdeletion of ∼145 kb at 3p22.1, disrupting the ULK4 gene, and a maternally inherited microduplication of ∼117 kb at Xq21.1 including only the BRWD3 gene. As already described for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counseling because of an evident variable penetrance. We discuss the possible correlations between the clinical phenotype of our patients and the function of the genes involved in these microrearrangements.

1.
Crespi B, Summers K, Dorus S: Genomic sister-disorders of neurodevelopment: an evolutionary approach. Evol Appl 2:81-100 (2009).
2.
Domínguez L, Schlosser G, Shen S: Expression of a novel serine/threonine kinase gene, Ulk4, in neural progenitors during Xenopus laevis forebrain development. Neuroscience 290:61-79 (2015).
3.
Field M, Tarpey PS, Smith R, Edkins S, O'Meara S, et al: Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am J Hum Genet 81:367-374 (2007).
4.
Fuccillo M, Joyner AL, Fishell G: Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7:772-783 (2006), Erratum in Nat Rev Neurosci 7:902 (2006).
5.
Grotto S, Drouin-Garraud V, Ounap K, Puusepp-Benazzouz H, Schuurs-Hoeijmakers J, et al: Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly. Eur J Med Genet 57:200-206 (2014).
6.
Jarome TJ, Kwapis JL, Hallengren JJ, Wilson SM, Helmstetter FJ: The ubiquitin-specific protease 14 (USP14) is a critical regulator of long-term memory formation. Learn Mem 21:9-13 (2013).
7.
Lang B, Pu J, Hunter I, Liu M, Martin-Granados C, et al: Recurrent deletions of ULK4 in schizophrenia: a gene crucial for neuritogenesis and neuronal motility. J Cell Sci 127:630-640 (2014).
8.
Lang B, Zhang L, Jiang G, Hu L, Lan W, et al: Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia. Sci Rep 6:31126 (2016).
9.
Liu M, Guan Z, Shen Q, Flinter F, Domínguez L, et al: Ulk4 regulates neural stem cell pool. Stem Cells 34:2318-2331 (2016a).
10.
Liu M, Guan Z, Shen Q, Lalor P, Fitzgerald U, et al: Ulk4 is essential for ciliogenesis and CSF flow. J Neurosci 36:7589-7600 (2016b).
11.
Liu M, Xu P, O'Brien T, Shen S: Multiple roles of Ulk4 in neurogenesis and brain function. Neurogenesis (Austin) 4:e1313646 (2017).
12.
Liu M, Fitzgibbon M, Wang Y, Reilly J, Qian X, et al: Ulk4 regulates GABAergic signaling and anxiety-related behavior. Transl Psychiatry 8:43 (2018a).
13.
Liu M, Xu P, Guan Z, Qian X, Dockery P, et al: Ulk4 deficiency leads to hypomyelination in mice. Glia 66:175-190 (2018b).
14.
Maloverjan A, Piirsoo M, Kasak L, Peil L, Østerlund T, Kogerman P: Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway. J Biol Chem 285:30079-30090 (2010).
15.
Merchant M, Evangelista M, Luoh SM, Frantz GD, Chalasani S, et al: Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 25:7054-7068 (2005).
16.
Oud MM, Lamers IJ, Arts HH: Ciliopathies: genetics in pediatric medicine. J Pediatr Genet 6:18-29 (2017).
17.
Ozturk N, VanVickle-Chavez SJ, Akileswaran L, Van Gelder RN, Sancar A: Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex. Proc Natl Acad Sci USA 110:4980-4985 (2013).
18.
Ro SH, Jung CH, Hahn WS, Xu X, Kim YM, et al: Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes. Autophagy 9:2103-2114 (2013).
19.
Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, et al: Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet 80:345-352 (2007).
20.
Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, et al: A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 41:535-543 (2009).
21.
Taylor RW, Qi JY, Talaga AK, Ma TP, Pan L, et al: Asymmetric inhibition of Ulk2 causes left-right differences in habenular neuropil formation. J Neurosci 31:9869-9878 (2011).
22.
Vogel P, Read RW, Hansen GM, Payne BJ, Small D, et al: Congenital hydrocephalus in genetically engineered mice. Vet Pathol 49:166-181 (2012).
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